Two distinct pathways of muscarinic current responses in rabbit sino-atrial node myocytes
Two distinct pathways of muscarinic current responses in rabbit sino-atrial node myocytes
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DOI：
10.1007/s004240050763
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发表时间：
1998-12-01
影响因子：
4.5
通讯作者：
DiFrancesco, D
中科院分区：
文献类型：
--
作者：
Accili, EA;Redaelli, G;DiFrancesco, D
乙酰胆碱（ACh）通过作用于窦房结电流来减慢心率。低浓度ACh作用于毒蕈碱受体，通过腺苷3 '，5'-环一磷酸（cAMP）依赖性细胞质途径抑制超极化激活电流（i（f））。乙酰胆碱还通过百日咳毒素敏感的鸟嘌呤核苷酸结合蛋白（G蛋白）激活毒蕈碱钾电导（i（K，ACh）），直接门控通道。这种途径被称为膜定界或“快速”，因为不需要细胞质组分，因此活化相对较快。这种途径也被提出用于i（f）的毒蕈碱抑制。在这里，我们表明，在稳态电流条件下，0.1-1 μ M乙酰胆碱激活i（K，乙酰胆碱）与1秒或更短的时间常数，是成反比的乙酰胆碱浓度，符合快速，膜界定的途径。ACh还导致对i（f）的抑制显著减慢，这与ACh结合不成比例。i（f）的变化与仅通过cAMP途径介导的毒蕈碱效应一致。
Acetycholine (ACh) slows the heart rate by acting on sino-atrial node currents. Low ACh concentrations act on muscarinic receptors to inhibit the hyperpolarization-activated current (i(f)) by a adenosine 3',5'-cyclic monophosphate (cAMP)-dependent cytoplasmic pathway. ACh also activates a muscarinic potassium conductance (i(K,ACh)) via a pertussis toxin-sensitive guanine nucleotide-binding protein (G-protein) that gates the channel directly. This pathway has been called membrane-delimited or "fast" because cytoplasmic components are not required and hence activation is relatively rapid. Such a pathway has also been proposed for the muscarinic inhibition of i(f). Here we show that, under steady-state current conditions, 0.1-1 mu M ACh activates i(K,ACh) with a time constant of 1 s or less that is inversely proportional to ACh concentration, consistent with a fast, membrane-delimited pathway. ACh also causes a significantly slower inhibition of i(f) which is not proportional to ACh binding. The changes in i(f) are consistent with muscarinic effects mediated exclusively through the cAMP pathway.